Abstract 3641: Age-related changes in microenvironmental collagen affect ovarian cancer metastasis
Authors: Elizabeth Harper, Elizabeth Agadi, Emma Sheedy, Preston Carey, Paul Wilkinson, Michael Siroky, Tyvette Hilliard, Ethan Low, Annemarie Leonard, Yueying Liu, Jing Yang, M. Sharon Stack
Journal: Cancer Research (2022)

Abstract Aging is the biggest risk factor for the development of ovarian cancer (OvCa), the deadliest cancer of the female reproductive system. Despite this, age is understudied in the OvCa field. Using a C57Bl/6 mouse model of aging, young (Y) mice ranging from 3-6 months of age and aged (A) mice ranging from 20-23 months of age were used to study the role aging has on metastasis. Fluorescently tagged C57Bl/6 syngeneic ID8trp53-/- mouse ovarian surface epithelial cancer cells were injected intraperitoneally in Y and A mice and disease progression was evaluated following 5.5 weeks. Organ-specific tumor burden was quantified with ImageJ, revealing increased tumor burden in A mice compared to their Y counterparts. These results were reproduced in the FVB mouse model using syngeneic PTENshRNA/KRASG12V oviductal epithelial cells. While in vitro assays showed no significant difference in adhesion or invasion of OvCa cells on Y vs A collagen, human cell lines showed increased invasion through Boyden invasion chambers lined with A collagen compared to Y. The relationship between tumors and aged collagen was further investigated by analysis of collagen hybridizing peptide (CHP) staining of paraffin-embedded omental tumor sections, which shows an increase of intratumoral collagen remodeling in A tumors despite no significant difference in overall collagen amount as shown by trichrome analysis of serial sections. However, second harmonic generation microscopy (SHG) and CHP fluorescence analysis of early tumor events shows increased peritumoral collagen remodeling in Y mice, showing a difference between intratumoral collagen and microenvironmental collagen. Immunohistochemical analysis of paraffin-embedded tumor sections showed similar amounts of advanced glycation end products (AGEs) and cancer-associated fibroblasts (CAFs) in Y and A tumors, suggesting intratumoral collagen is newly synthesized by CAFs whereas the collagen in the microenvironment is truly aged. To further investigate peritumoral collagen in the metastatic microenvironment, SHG was used to visualize collagen of common metastatic sites from Y and A tumor naïve C57Bl/6 mice. Distinct structural differences were shown in omental collagen in the Y vs A cohorts and validated with scanning electron microscopy (SEM). In conclusion, aging induces changes in the structure and properties of both intra- and peritumoral collagen, increasing OvCa metastatic success. Citation Format: Elizabeth Harper, Elizabeth Agadi, Emma Sheedy, Preston Carey, Paul Wilkinson, Michael Siroky, Tyvette Hilliard, Ethan Low, Annemarie Leonard, Yueying Liu, Jing Yang, M. Sharon Stack. Age-related changes in microenvironmental collagen affect ovarian cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3641.